PROJECT SUMMARY: No cure currently exists for high grade gliomas, which have a mean survival time of approximately 1 year from diagnosis. These tumors are highly aggressive and invasive, despite current treatment protocols. Noncanonical NF-?B signaling has been linked to glioma progression, but the downstream consequences of activation of this pathway have not been completely defined. Thus, a better understanding of the key molecular signals that regulate the invasive nature of glioma could aid in intervening in these clinical situations. This proposal will examine whether the NF-?B-inducing kinase (NIK) enhances the leader cell phenotype in glioma to increase collective cell migration, which facilitates tumor invasion of surrounding normal tissue. Based on previous and preliminary findings, we hypothesize that NIK and noncanonical NF-?B signaling promotes the acquisition of invasive potential in leader cells responsible for tumor dissemination through upregulation of the ?11 integrin subunit (ITGA11) and MT1-MMP activity. The enclosed aims will test whether noncanonical NF-?B signaling enhances ITGA11 expression and pseudopodial localization, and also determine the functional significance of noncanonical NF-?B controlled ITGA11 expression on glioma cell invasion. We will use complementary approaches that involve the use of primary human brain tumor lines in vitro and in vivo. These studies are expected to show that NIK and noncanonical NF-?B signaling simultaneously enhances ECM recognition and degradation via ITGA11/MT1-MMP complexes in the mesenchymal subtype of glioma to facilitate tumor dissemination. These studies will contribute to our long-term goal of an improved understanding of the molecular signals that initiate cell migration in three- dimensions and glioma progression.